U.S. patent number 5,349,064 [Application Number 08/029,310] was granted by the patent office on 1994-09-20 for production of pyrrolopyrimidines.
This patent grant is currently assigned to Takeda Chemical Industries, Ltd.. Invention is credited to Hiroshi Akimoto, Takenori Hitaka, Tetsuo Miwa.
United States Patent |
5,349,064 |
Akimoto , et al. |
September 20, 1994 |
Production of pyrrolopyrimidines
Abstract
There is provided an improved process for producing novel
compounds represented by the general formula: ##STR1## wherein the
ring A represents a pyrrole ring which may be hydrogenated; X
represents an amino, hydroxyl or mercapto group; R.sup.1, R.sup.2
and R.sup.3 each being the same as or different from the other,
represents hydrogen or an alkyl, alkenyl or alkynyl group which may
be substituted; R.sup.4 represents OR.sup.5 wherein R.sup.5
represents hydrogen or a hydrocarbon group which may be substituted
or NHCH(COOR.sup.6)CH.sub.2 CH.sub.2 COOR.sup.7 wherein R.sup.6 and
R.sup.7 each represents hydrogen or a hydrocarbon group which may
be substituted; and n represents an integer of 1 to 4, or a salt
thereof from compounds represented by the general formula: ##STR2##
wherein X, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n are the same as
defined above; Y.sup.1 and Y.sup.2 each represents oxygen or sulfur
atom; R.sup.8 and R.sup.9 each, being the same as or different from
the other, represents a hydrocarbon group which may be substituted,
or salts thereof by an intramolecular ring closure reaction to form
a pyrrolopyrimidine ring and, if necessary, reducing the pyrrole
ring thus formed to a pyrroline ring. The compounds are useful as
antitumor agents.
Inventors: |
Akimoto; Hiroshi (Kobe,
JP), Hitaka; Takenori (Takarazuka, JP),
Miwa; Tetsuo (Kobe, JP) |
Assignee: |
Takeda Chemical Industries,
Ltd. (JP)
|
Family
ID: |
27307029 |
Appl.
No.: |
08/029,310 |
Filed: |
March 8, 1993 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
537807 |
Jun 14, 1990 |
|
|
|
|
Foreign Application Priority Data
|
|
|
|
|
Jun 14, 1989 [JP] |
|
|
1-150910 |
Sep 18, 1989 [JP] |
|
|
1-242975 |
Apr 6, 1990 [JP] |
|
|
2-92391 |
|
Current U.S.
Class: |
544/280 |
Current CPC
Class: |
C07D
487/04 (20130101); A61P 35/00 (20180101); C07D
239/50 (20130101); C07D 239/48 (20130101) |
Current International
Class: |
C07D
487/04 (20060101); C07D 239/00 (20060101); C07D
239/50 (20060101); C07D 239/48 (20060101); C07D
487/00 (20060101); C07D 487/04 () |
Field of
Search: |
;544/280 |
Foreign Patent Documents
|
|
|
|
|
|
|
0268377 |
|
May 1988 |
|
EP |
|
0325343 |
|
Jul 1989 |
|
EP |
|
0334636 |
|
Sep 1989 |
|
EP |
|
0340905 |
|
Nov 1989 |
|
EP |
|
812366 |
|
Apr 1959 |
|
GB |
|
Other References
Journal of the Chemical Society, 1960, Part I, pp. 131-138, J.
Davoll, Pyrrolo[2,3-d]pyrimidines. .
Agricultural and Biological Chemistry, vol. 41, 1977, pp.
1501-1507, T. Kondo et al. "Synthesis of 5-Methyltubercidin and Its
.alpha.-Anomer via Condensation of the Anion of
4-Methoxy-5-methyl-2-methyl-thiopyrrolo [2,3-d]pyrimidine and
2,3,5-Tri-O-benzyl-D-ribofuranosyl Bromide". .
Chemical Abstracts, vol. 112, No. 11, Mar. 12, 1990, p. 815,
99168b. .
Chemische Berlichte, vol. 110 (1977) pp. 1462-1469 (translation),
1977. .
"The Chemistry of the Carbonyl Group", vol. 2, (1970) Interscience
Publishers, pp. 19-20, 1970. .
"Advanced Organic Chemistry" by March pp. 796-797 (1985) published
by John Wiley and Sons. .
"Rodd's Chemistry of Carbon Compounds" edited by Coffey vol. IV,
Part A, pp. 329-333, 402-403 (1973) Elsevier Scientifc Publishing
Company..
|
Primary Examiner: Ford; John M.
Assistant Examiner: Gupta; Y. N.
Attorney, Agent or Firm: Wegner, Cantor, Mueller &
Player
Parent Case Text
This application is a continuation of United States application
Serial No. 07/537,807 filed Jun. 14, 1990 now abandoned.
Claims
We claim:
1. A process for producing a compound represented by the formula:
##STR15## The ring A represents a pyrrole ring which may be
hydrogenated; X represents an amino, hydroxyl or mercapto
group;
R.sup.1 represents hydrogen or a C.sub.1-6 alkyl group which may be
substituted; R.sup.2 and R.sup.3 each, being the same or different,
represents hydrogen or a C.sub.1-6 alkyl, C.sub.2-6 alkenyl or
C.sub.2-6 alkynyl group which may be substituted;
R.sup.4 represents OR.sup.5 wherein R.sup.5 represents hydrogen or
a hydrocarbon group selected from the group consisting of C.sub.1-5
alkyl, benzyl and phenyl which may be substituted or
NHCH(COOR.sup.6)CH.sub.2 CH.sub.2 COOR.sup.7 wherein R.sup.6 and
R.sup.7 each represents hydrogen or a hydrocarbon group selected
from the group consisting of C.sub.1-5 alkyl, benzyl and phenyl
which may be substituted; and n represents an integer of i to
4,
or a nontoxic salt thereof,
said process comprising contacting a compound of the formula:
##STR16## wherein X, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n are
the same as defined above; Y.sup.1 and Y.sup.2 each represents
oxygen or sulfur atom; R.sup.8 and R.sup.9 each, being the same or
different, represents a hydrocarbon group selected from the group
consisting of C.sub.1-5 alkyl, benzyl and phenyl which may be
substituted, or a salt thereof, with an acid in a water-containing
organic solvent to undergo a ring-closure reaction, wherein during
said ring-closure reaction the group ##STR17## is converted to a
carbonyl, hemiacetal or hemiketal group, said carbonyl, hemiacetal
or hemiketal group condensing with the amino group on the
pyrimidine ring to form the pyrrolo(2,3-d)pyrimidine ring, and
optionally, reducing the pyrrole ring of ring A into a pyrroline
ring, or converting OR.sup.5 of R.sup.4, where R.sup.5 is the same
as defined above, into, NHCH(COOR.sup.6)CH.sub.2 CH.sub.2
COOR.sup.7 where R.sup.6 and R.sup.7 are the same as defined
above,
wherein in the above formulae, the substituted alkyl, substituted
alkenyl and substituted alkynyl groups of R.sup.1, R.sup.2,
R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are
substituted with one to three substituents selected from the group
consisting of halogen, nitro, cyano, alkoxy of 1 to 4 carbon atoms,
alkanoyl of 1 to 4 carbon atoms, alkanoyloxy of 1 to 4 carbon
atoms, alkoxycarbonyl of 2 to 4 carbon atoms, trifluoromethyl,
alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon
atoms and alkylsulfonyl of 1 to 4 carbon atoms; and wherein the
substituted phenyl and substituted benzyl groups of R.sup.5,
R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are substituted with one to
three substituents selected from the group consisting of halogen,
nitro, cyano, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4
carbon atoms, alkanoyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of
2 to 4 carbon atoms, trifluoromethyl, alkythio of 1 to 4 carbon
atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to
4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 3
carbon atoms and alkynyl of 2 to 3 carbon atoms.
2. A process as claimed in claim 1, wherein the water-containing
organic solvent is a mixture of an alcohol, an acetic acid ester,
an ether, a ketone, an amide, a sulfoxide or a nitrile with
water.
3. A process as claimed in claims 1, wherein the acid is selected
from the group consisting of hydrogen chloride, hydrogen bromide,
perchloric acid, sulfuric acid, nitric acid and phosphoric
acid.
4. A process as claimed in claim 1, wherein R.sup.1, R.sup.2 and
R.sup.3 each is a hydrogen atom.
5. A process as claimed in claim 1, wherein Y.sup.1 and Y.sup.2 and
both are an oxygen atom.
6. A process as claimed in claim 1, wherein R.sup.8 and R.sup.9
each is a C.sub.1-3 alkyl group.
7. A process as claimed in claim 1, wherein R.sup.5, R.sup.6 and
R.sup.7 each is a C.sub.1-5 alkyl group or benzyl group.
Description
This invention relates to a process for producing novel
pyrrolo[2,3-d]pyrimidine derivatives which are useful as an
antitumor agent, novel intermediates and production method of the
derivatives.
Folic acid, acting as a transferring agent of one-carbon (C1) units
derived from formic acid, formaldehyde, etc. in living bodies,
plays a role as a coenzyme in various enzymic reaction systems,
such as nucleic acid biosynthesis, amino acid peptide metabolism
and methane formation systems. In the nucleic acid biosynthesis
system, particularly, the compound is essential for the formylation
reaction in the two biosynthetic pathways for nucleic acids, i.e.
the purine nucleotide pathway and thymidine nucleotide pathway. In
order to demonstrate its biological activities, folic acid must
ordinarily undergo reduction in two steps to be converted into the
active coenzyme form. Amethopterin (methotrexate: MTX) and
analogous compounds are known as drugs that bind strongly to the
enzyme (dihydrofolate reductase) controlling its second stage and
thus suppress reduction of dihydrofolic acid to tetrahydrofolic
acid. These drugs, which act to impair the DNA synthesis, resulting
in cell death, have been developed as an antitumor agent and
currently occupy an important position established as a clinical
agent. On the other hand, there has been reported a novel
tetrahydroaminopterine antitumor agent
(5,10-dideaza-5,6,7,8-tetrahydroaminopterine: DDATHF), which
possesses the basic skeleton of the pteridine ring but, unlike the
mechanism of action of such structurally analogous drugs, does not
exhibit inhibitory activity against dihydrofolate reductase and
acts mainly through the mechanism of inhibiting glycinamide
ribonucleotide transformylase being involved in the initial stage
of the purine biosynthesis pathway (Journal of Medicinal Chemistry
28, 914 (1985)).
MTX, an antitumor agent that acts principally through the mechanism
as a folic acid antagonist, has long been put in frequent use
conventionally as a clinical agent. Nevertheless, it, because of
its relatively strong toxicity and inferior efficacy against solid
tumors, has failed to achieve satisfactory therapeutic effects. In
addition, it has been encountered with the always more serious
problem of acquired resistance of tumor cells to the drug. To be
particularly expected at present is the development of antitumor
drug substances which can demonstrate improved efficacy and
enhanced selective toxicity against cancer cells on the basis of a
new action mechanism. The present inventors, in view of the above
circumstances, have conducted repeated extensive research on the
process for producing non-pteridine ring compounds as well as the
antitumor activity of such compounds. As a result, the present
inventors established novel processes for producing 5-substituted
pyrrolo[2,3-d]pyrimidine derivatives, which are industrially
advantageous in yield, selectivity in pyrrole-ring formation, etc.,
and also found that a variety of novel compounds produced by such
production process can exhibit potent growth-inhibitory activity
against human tumor cells. On the basis of the foregoing, this
invention has been established.
Thus, this invention is directed to:
(1) A process for producing a compound represented by the general
formula: ##STR3## wherein the ring A represents a pyrrole ring
which may be hydrogenated; X represents an amino, hydroxyl or
mercapto group; R.sup.1, R.sup.2 and R.sup.3 each, being the same
as or different from the other, represents hydrogen or an alkyl,
alkenyl or alkynyl group which may be substituted; R.sup.4
represents OR.sup.5 (wherein R.sup.5 represents hydrogen or a
hydrocarbon group which may be substituted) or
NHCH(COOR.sup.6)CH.sub.2 CH.sub.2 COOR.sup.7 (wherein R.sup.6 and
R.sup.7 each represents hydrogen or a hydrocarbon group which may
be substituted); and n represents an integer of 1 to 4, or a salt
thereof characterized in that the said process comprises allowing a
compound represented by the general formula: wherein X, R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and n are the same as defined above;
Y.sup.1 and Y.sup.2 each represents oxygen or sulfur atom; R.sup.8
and R.sup.9 each, being the same as or different from the other,
represents a hydrocarbon group which may be substituted, or a salt
thereof to undergo a ring-closure reaction in the course or after
regeneration of the group ##STR4## in the compound to a carbonyl
group to thereby form the pyrrolo[2,3-d]pyrimidine ring, and,
furthermore, if necessary, reducing the pyrrole ring of ring A into
a pyrroline ring, or/and converting OR.sup.5 of R.sup.4 where
R.sup.5 is the same as defined above into NHCH(COOR.sup.6)CH.sub.2
CH.sub.2 COOR.sup.7 where R.sup.6 and R.sup.7 are the same as
defined above,
(2) Compounds (II) as described in the preceding item (1);
(3) A process as described in preceding item (1) for producing a
compound represented by the general formula: ##STR5## wherein X is
an amino, hydroxyl or mercapto group; R.sup.1, R.sup.2 and R.sup.3
each, being the same as or different from the other, represents
hydrogen, or an alkyl, alkenyl or alkynyl group which may be
substituted; R.sup.4 is OR.sup.5 wherein R.sup.5 represents
hydrogen or a hydrocarbon group which may be substituted or
NHCH(COOR.sup.6)CH.sub.2 CH.sub.2 COOR.sup.7 wherein R.sup.6 and
R.sup.7 each represents hydrogen or a hydrocarbon group which may
be substituted; and n is an integer of 1 to 4 or a salt thereof
characterized in that the said process comprises (i) catalytically
reducing a compound of the general formula, ##STR6## wherein X,
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n are the same as defined
above; R.sup.8 and R.sup.9 each, being the same as or different
from the other, represents a hydrocarbon group which may be
substituted; and Y.sup.1 and Y.sup.2 each represents oxygen or
sulfur atom, or a salt thereof,
(ii) contacting the said compound or a salt thereof with an acid or
a metal salt, or
(iii) reacting tile said compound or a salt thereof with an
oxidizing agent; and,
(4) A process for producing a compound represented by the general
formula, ##STR7## wherein X represents an amino, hydroxyl or
mercapto group; R.sup.1, R.sup.2 and R.sup.3 each, being the same
as or different from the other, represents hydrogen, or an alkyl,
alkenyl or alkynyl group which may be substituted; R.sup.4
represents OR.sup.5 where R.sup.5 represents hydrogen or a
hydrocarbon group which may be substituted or
NHCH(COOR.sup.6)CH.sub.2 CH.sub.2 COOR.sup.7 wherein R.sup.6 and
R.sup.7 each represents hydrogen or a hydrocarbon group which may
be substituted; n represents an integer of 1 to 4, R.sup.8 and
R.sup.9 each, being the same as or different from the other,
represents a hydrocarbon group which may be substituted; and
Y.sup.1 and Y.sup.2 each represents oxygen or sulfur atom, or a
salt thereof, characterized in that the said process comprises
reacting a compound of the formula, ##STR8## wherein E represents
CN, COOR.sup.10, CSOR.sup.10, or CSSR.sup.10 wherein R.sup.10
represents a hydrocarbon group which may be substituted; and other
symbols are the same as defined above, with guanidine or its
salt.
The compounds (I) and (II) of the above general formulae where X is
a hydroxy or mercapto group can exist in the form of the
equilibrium mixture with their tautomers. Given below are the
structural formulae of the moiety which are susceptible to
tautomerism in relation to X, with the equilibrium relationship
between them being shown, as well. ##STR9## For the convenience of
representation, the hydroxy and mercapto forms are described
throughout this specification and the corresponding system of
nomenclature is adopted, however, it is to be understood that, in
both cases, the oxo and thioxo isomers, or tautomers, are included
as well.
Although a plurality of asymmetric molecules can exist in the
compounds (I) and (II) of this invention, the absolute
configurations of such asymmetric centers may be the S- or R-form
or a mixture of the R- and S-forms, except the asymmetric carbon
atom in the side chain derived from glutamic acid represented by
R.sup.4 has the absolute configuration of S(L). In this case, a
plurality of diastereomers exist, and can be easily separated by
the conventional separation and purification means, if necessary.
The above described diastereomers, which can be separated by such
procedures, are all included within the scope of this
invention.
Referring to the above formulae, X represents an amino, hydroxyl or
mercapto group, and frequently used is the amino group; the alkyl,
alkeny or alkynyl group represented by R.sup.1, R.sup.2 and R.sup.3
includes an alkyl group of 1 to 6 carbon atoms (e.g., methyl,
ethyl, propyl and iso-propyl groups); alkenyl groups of 2 to 6
carbon atoms (e.g., vinyl, 1-methylvinyl, 1-propenyl, allyl and
allenyl groups); and alkynyl groups of 2 to 6 carbon atoms (e.g.,
ethynyl, 1-propynyl and propargyl groups), respectively, whereby
these groups as represented by R.sup.2 and R.sup.3 may be different
individually in the repeating units shown by n.
The preferred examples of R.sup.1, R.sup.2 and R.sup.3 are hydrogen
and the like. n represents an integer of 1 to 4 and may preferably
represents 2 or 3.
R.sup.5 in the OR.sup.5 group represented by R.sup.4 as well as
R.sup.6 and R.sup.7 in the NHCH(COOR.sup.6)CH.sub.2 CH.sub.2
COOR.sup.7 designate hydrogen or a hydrocarbon group which may be
substituted, respectively. As the hydrocarbon group, there may be
mentioned, for example, a lower alkyl group of I to 5 carbon atoms
(e.g., methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neopentyl
and tert-pentyl groups) and benzyl or phenyl groups. The preferable
examples of R.sup.4 include groups represented by the formulas
O.sup.5a or --NHCH(COOR.sup.6a)CH.sub.2 CH.sub.2 COOR.sup.7a (where
OR.sup.5a, R.sup.6a and R.sup.7a each represents, for example, a
C.sub.1-3 alkyl group such as methyl and ethyl, or benzyl group)
and the like.
Y.sup.1 and Y.sup.2, each being the same as or different from the
other, represents oxygen or sulfur and both desirably designate
oxygen. The hydrocarbon group represented by R.sup.8 or R.sup.9
includes a lower alkyl of 1 to 5 carbon atoms, benzyl or phenyl
group as described in detail for R.sup.5, R.sup.6 and R.sup.7 and
among them, frequently used is a C.sub.1-3 alkyl group as methyl
and ethyl.
Alkyl, alkenyl and alkynyl groups represented by the above R.sup.1,
R.sup.2, R.sup.3 as well as hydrocarbon groups represented by
R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 may have 1 to 3
substituents. Such substituents include, for example, halogen atoms
(e.g., fluorine, chlorine, bromine and iodine), nitro group, cyano
group, alkoxy groups of about 1 to 4 carbon atoms (e.g., methoxy,
ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and
tert-butoxy groups), alkanoyl groups of about 1 to 4 carbon atoms
(e.g., formyl, acetyl, propionyl, n-butyryl and iso-butyryl
groups), alkanoyloxy groups of about 1 to 4 carbon atoms (e.g.,
formyloxy, acetyloxy, propionyloxy, n-butyryloxy and iso-butyryloxy
groups), alkoxycarbonyl groups of about 2 to 4 carbon atoms (e.g.,
methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
iso-propoxycarbonyl, n-butoxycarbonyl, iso-butoxycarbonyl and
tert-butoxycarbonyl groups), trifluoromethyl group, alkylthio
groups of about 1 to 4 carbon atoms (e.g., methylthio, ethylthio,
propylthio, isopropylthio, n-butylthio, sec-butylthio and
tert-butylthio groups), alkylsulfinyl groups of about 1 to 4 carbon
atoms (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl and
butylsulfinyl groups), alkylsulfonyl groups of about 1 to 4 carbon
atoms (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl and
butylsulfonyl groups) and the like. In the case that R.sup.5,
R.sup.6, R.sup.7, R.sup.8 or R.sup.9 is benzyl or phenyl group, it
may be substituted by alkyl groups of 1 to 4 carbon atoms (e.g.,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and
tert-butyl groups), alkenyl groups of 1 to 3 carbon atoms (e.g.,
methylene, vinyl, 1-methylvinyl, 1-propenyl, allyl and allenyl
groups), alkynyl groups of 2 to 3 carbon atoms (e.g., ethynyl,
1-propynyl and propargyl groups) and the like.
Given in the following is a detailed description of the process for
producing the compounds (I) or their salts of this invention.
##STR10##
In the steps of producing the compounds (I) or their salts of this
invention, the reaction of regenerating the group ##STR11## in the
compounds (II) or their salts to the carbonyl group ( C.dbd.O) can
be carried out by allowing the compound (II) or its salt to undergo
a decomposition reaction, as such or in the presence of a suitable
reaction solvent, at a reaction temperature in the range of about
-40.degree. C. to the boiling point (up to about 150.degree. C.) of
such reaction solvent, preferably about -10.degree. C. to
75.degree. C. for a length of time of about 10 minutes to 100
hours, preferably about 30 minutes to 24 hours. As the said
decomposition reaction, there may be mentioned, for example, the
catalytic reduction reaction (Method A), hydrolysis reaction under
acidic conditions (Method B-1) or decomposition reaction under
acidic, nonaqueous conditions (Method B-2), and decomposition
reaction making use of metal salt (Method C-1) or decomposition
reaction making use of oxidizing agent (Method C-2), and
particularly preferable is Method B-1 or B-2,
The amount of catalyst employed in Method A is usually about 0,005
to 2.0 moles, preferably about 0.01 to 0.5 mole to 1 mole of the
compound to be reduced. As the catalyst, there may be utilized
palladium, platinum, rhodium, Raney nickel and the like, whereby
the addition of trace amounts of acid (e.g., acetic acid,
trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc.) also
permits the reaction to proceed favorably. The amount of the acid
used in Method B-1 is usually about 0.01 to 100 moles, preferably
about 0.1 to 10 moles to 1 mole of the compound to be hydrolyzed,
and the examples of the acid include mineral acids, such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and
phosphoric acid; and organic acids, such as trifluoroacetic acid,
trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid and camphorsulfonic acid, etc., and, in
particular, a mineral acid such as hydrochloric acid, etc. is
frequently used.
The amount of the acid used in Method B-2 is usually about 0.01 to
10 moles, preferably about 0.1 to 2 moles to 1 mole of the compound
to be decomposed, and the examples of the acid are mineral acids,
such as hydrogen chloride, hydrogen bromide, perchloric acid,
sulfuric acid, nitric acid, phosphoric acid, etc.; organic acids,
such as trifluoroacetic acid, trichloroacetic acid, methanesulfonic
acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic
acid, etc.; and Lewis acids, such as anhydrous zinc chloride,
anhydrous aluminum chloride (AlCl.sub.3), anhydrous ferric
chloride, titanium tetrachloride (TICl.sub.4), tin tetrachloride
(SnCl.sub.4), antimony pentachloride, cobalt chloride, cupric
chloride, boron trifluoride-diethyl ether, etc.
The amount of metal salts used in Method C-1 is usually about 0.1
to 10 equivalents, preferably about 0.5 to 2 equivalents to 1 mole
of the compound to be decomposed, and the examples of the metal
salts include cupric chloride, silver nitrate, silver oxide,
mercuric chloride, tellurium salts (e.g., tellurium nitrate,
tellurium trifluoroacetate,), etc.
The amount of oxidizing agents used in Method C-2 is usually about
0.25 to 10 equivalents, preferably 0.25 to 2 equivalents per mole
of the compound to be oxidized, and the examples of the oxidizing
agents include oxygen-light, hydrogen peroxide, perbenzoic acid,
m-chloroperbenzoic acid, perchlorates (lithium perchlorate, silver
perchlorate, mercuric perchlorate, tetrabutylammonium perchlorate,
etc.), nitrosylsulfuric acid, alkylnitrite acid (e.g.,isoamyl
nitrite, etc.), iodine, bromine, chlorine, N-bromosuccinimide,
sulfuryl chloride, chloramine T, etc.
Referring to the reaction solvent, usable in Methods A and B-1 are,
for example, water, alcohols (e.g., methanol, ethanol, propanol,
iso-propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol,
ethylene glycol, methoxyethanol, ethoxyethanol), acetic acid esters
(e.g., methyl acetate, ethyl acetate), ethers (e.g., dimethyl
ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme,
diglyme), aromatic hydrocarbons (e.g., benzene, toluene, xylene),
ketones (e.g. acetone), nitriles (e.g., acetonitrile), pyridine,
amides (e.g., dimethylformamide, dimethylacetamide), sulfoxides
(e.g., dimethylsulfoxide), sulfolane and suitable solvent mixture
thereof: In the case of Method A, preferably used is methanol,
ethanol, ethyl acetate, tetrahydrofuran, dioxane or benzene, and in
the case of Method B-1, there is frequently used a water-containing
organic solvent wherein 0.01 to 100 g, preferably 0.1 to 10 g of a
hydrophilic solvent, preferably an alcohol such as methanol,
ethanol, etc., an acetic acid ester such as ethyl acetate, an ether
such as tetrahydrofuran, dioxane, etc., a ketone such as acetone,
etc., or a nitrile such as acetonitrile, etc. is contained together
with 1 g of water.
These solvents are employed in an amount of usually 1.0 to 2,000
ml, preferably 5.0 to 100 ml to 1 g of the compound (II) or its
salt.
In the case of Method B-2, there may be utilized, for example,
acetic acid esters (e.g., methyl acetate, ethyl acetate), ethers
(e.g., dimethyl ether, diethyl ether, tetrahydrofurane, dioxane,
monoglyme, diglyme), aromatic hydrocarbons (e.g., benzene, toluene,
xylene), halogenated hydrocarbons (e.g., dichloromethane,
chloroform, carbon tetrachloride), ketones (e.g. acetone), nitriles
(e.g. acetonitrile), nitromethane, pyridine, dimethylformamide or
suitable solvent mixtures thereof; and preferable solvents are
aromatic hydrocarbons such as benzene, toluene, etc., halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, etc., or nitriles such as acetonitrile, etc.
In the event of employing Methods C-1 and C-2, there are usable,
for example, water, alcohols (e.g., methanol, ethanol, propanol,
iso-propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol,
ethylene glycol, methoxyethanol, ethoxyethanol), ethers (e.g.,
dimethyl ether, diethyI ether, tetrahydrofuran, dioxane, monoglyme,
diglyme), aromatic hydrocarbons (e.g., benzene, toluene, xylene),
halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon
tetrachloride, etc.), acetone, acetonitrile and suitable solvent
mixtures thereof. In any of Methods C-1 and C-2, preferable
solvents are methanol, ethanol, tetrahydrofuran, dioxane or
acetonitrile, and a mixture of thus solvent and water. What method
should be applied to regenerate the carbonyl group ( =CO) can
suitably be determined depending on the chemical properties, etc.
of --Y.sup.1 --R.sup.8 and --Y.sup.2 --R.sup.9, and usually Method
B-1 is frequently used as more preferable method.
In the intramolecular ring-closure reaction in the steps of
producing the compounds (I) or their salts of this invention,
during or after regeneration to a carbonyl group ( C=O), usually
the carbonyl group condenser spontaneously with the amino group on
the pyrimidine ring to thereby form the pyrrolo[2,3-d]pyrimidine
ring. Particularly, in Methods B-1 and B-2, the regeneration of the
carbonyl group and intermolecular ring-closure reaction proceed
rapidly, resulting in advantageous yield of the product. In Methods
A, C-1 and C-2, the presence of an acid catalyst permits the
ring-closure reaction to proceed quickly and in improved yields. As
such a acid catalyst, there can be mentioned the mineral acids,
organic acids or Lewis acids as described in detail for Methods B-1
and B-2.
The compound (I-1) thus obtained wherein ring A is a pyrrole ring
can be easily converted, if necessary, to the compound (I-2)
wherein the ring A is a pyrroline ring by a catalytic reduction. As
the catalytic reduction reaction, Method A as described above can
be advantageously applied as such.
The compound (I-1) or (I-2) or their salts wherein R.sup.4 is
OR.sup.5 where R.sup.5 is a hydrocarbon group which may be
substituted can also be subjected to the socalled ester
decomposition or hydrolysis reaction to thereby produce the
compound where R.sup.5 is hydrogen, followed by conversion to the
compound wherein R.sup.4 is an NHCH(COOR.sup.6)CH.sub.2 CH.sub.2
COOR.sup.7. The ester decomposition reaction as well as the
conversion reaction to the NHCH(COOR.sup.6)CH.sub.2 CH.sub.2
COOR.sup.7 group can be conducted by the per se known procedures
[J. F. W. McOmine, "Protective Groups in Organic Chemistry", Plenum
Press, London and New York (1973); and M. Fieser and L. Fieset,
"Reagents for Organic Synthesis", vols. 1 to 13,
Wiley-Interscience, New York, London, Sydney and Toronto
(1969-1988)].
In the compounds (I) and (II) or their salts, furthermore, the
amino, hydroxyl or mercapto group represented by X each can be
converted to the other by the substituent conversion reaction on
the pyrimidine ring as known in literature [a separate volume of
Tanpakushitsu Kakusan Kohso (Protein, Nucleic Acids and Enzymes),
"Chemical Synthesis of Nucleic Acids", Kyoritsu Publishing Co.
(1968)].
The compound (I) or its salt of this invention produced by the
above procedure can be isolated or purified from the reaction
mixture by usual means, for example, concentration, extraction with
a solvent, chromatography, recrystallization, etc.
The compounds (II) or their salts of this invention, which are
utilized as intermediates in the process of this invention can be
produced, for example, by the reaction steps as shown in the
following. ##STR12##
In the above formulae, Y.sup.1, Y.sup.2, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.8, R.sup.9 and n are as defined above. E represents
an CN group or COOR.sup.10, CSOR.sup.10 or CSSR.sup.10 (wherein
R.sup.10 is a hydrocarbon group which may be substituted, while Z
is a halogen atom (e g , chlorine, bromine, iodine)) As R.sup.10 in
the COOR.sup.10, CSOR.sup.10 or CSSR.sup.10 group, there may be
mentioned, for example, the hydrocarbon groups which may be
substituted as described in detail for R.sup.5 to R.sup.9, and
preferable groups are C.sub.1-4 alkyl groups such as methyl and
ethyl groups, etc. or benzyl group etc. The above reaction steps
are described in detail in the following;
Step A
The step involves a step of allowing ##STR13## to add to the double
bond (R.sup.8 --Y.sup.1 --C.dbd.CH--) of the compound (III) to
produce the compound (IV). The amount of ##STR14## to be used
against the compound (III) usually ranges from about 0.5 to 4 mole
equivalents, preferably from about 0.8 to 1.5 mole equivalents.
This reaction can be carried out, in the presence of a suitable
solvent, at a reaction temperature in the range of about
-10.degree. C. to the boiling point (up to about 150.degree. C.) of
the reaction solvent used, preferably about 0.degree. C. to
100.degree. C., for about 30 minutes to 48 hours. The solvent to be
utilized in the reaction includes, for example, alcohols (e.g.,
methanol, ethanol), ethers (e.g., dimethyl ether, diethyl ether,
tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (e.g.,
acetonitrile), esters (e.g., ethyl acetate), halogenated
hydrocarbons (e.g., dichloromethane, chloroform, carbon
tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene,
xylene) or suitable solvent mixtures thereof. In carrying out the
reaction, exposure of light or addition of organic peroxides can
also permit the reaction to proceed more advantageously. The said
organic peroxides include, for example, t-butyl hydroperoxide,
peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc. The
compound (IV) obtained by such procedure is relatively reactive,
and may be isolated at this stage by usual means as described
above, but can also be utilized in the subsequent step directly
without being isolated.
Step B
The compound (IV) obtained in the step A can be reacted with
alcohols or thiols represented by R.sup.9 --Y.sup.2 --H in the
presence of a suitable solvent at a reaction temperature in the
region of about -10.degree. C. to the boiling point (up to about
100.degree. C.) of the reaction solvent, preferably about 0.degree.
C. to 50.degree. C., for about 10 minutes to 24 hours to be
converted to the compound (V). As the solvent to be used in the
reaction, there may be used, for example, ethers (e.g., dimethyl
ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme,
diglyme), nitriles (e.g., acetonitrile), esters (e.g., ethyl
acetate), halogenated hydrocarbons (e.g., dichloromethane,
chloroform, carbon tetrachloride), aromatic hydrocarbons (e.g.,
benzene, toluene, xylene, etc.) or suitable solvent mixtures
thereof. In addition, the alcohols or thiols themselves as
represented by R.sup.9 --Y.sup.2 --H may be utilized in excess as
the solvent. The compound (V) thus obtained may be isolated from
the reaction mixture by usual means as described above, but the
reaction mixture as it is may be utilized as a raw material in the
next step.
Step C
The compound (V), upon treatment with guanidine or its salt (e.g.,
a salt with an acid as described in the above Method B-1, etc.) in
a suitable solvent, undergoes reaction with its cyano, ester or
thioester group and gives rise to cyclization simultaneously to
form a pyrimidine ring, thereby yielding the compound (II) or its
salt of this invention. This reaction proceeds at a reaction
temperature of 0.degree. to 150.degree. C. , preferably 20.degree.
to 100.degree. C., for a reaction time in the range of 1 to 48
hours. The reaction, when conducted under basic conditions, can
also be allowed to proceed advantageously. The base used for making
the conditions, includes, for example, metal alkoxides, such as
sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. As
the reaction solvent, there may be used, for example, methanol,
ethanol, propanol, tert-butyl alcohol, dimethyl sulfoxide,
hexamethylphosphoramide or suitable solvent mixtures thereof,
etc.
The compound (II) of this invention as well as the starting or
intermediate compounds (III) to (V) as produced in these steps can
be isolated or purified from the corresponding reaction mixtures by
use of conventional separation and purification means, such as
concentration, solvent extraction, chromatography,
recrystailization, etc.
The compound (I) and the compound (II) obtained by the production
process according to this invention or an intermediate thereof, may
be in the form of salts, preferably pharmaceutically acceptable
salts. As the base salts, there may be mentioned, for example,
salts with alkali metals, alkaline earth metals, non-toxic metals,
ammonium and substituted ammoniums, such as sodium, potassium,
lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethyl
ammonium, triethyl ammonium, triethanol ammonium, pyridinium or
pyridinium substituted with, e.g., carbamoyl group or halogen such
as chlorine, bromine, etc. The acid salts include, for example,
salts with mineral acids, such as hydrochloric acid, sulfuric acid,
nitric acid, phosphoric acid and boric acid, and organic acids,
such as oxalic acid, tartaric acid, acetic acid, trifluoroacetic
acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic
acid and camphorsulfonic acid, and the like.
The compounds (I) or their salts exhibit excellent antitumor
activity against mice tumor cell lines (P388, L1210, L5178Y, B16
melanoma, MethA, Lewis Lung Carcinoma, S180 sarcoma, Ehrlich
Carcinoma and Colon 38) and human tumor cell lines (HL60 and KB),
while at the same time, they possesse reductive activity against
tumors (e.g., melanoma, sarcoma, mastocytoma, carcinoma, neoplasia,
etc.) attacking warm-blooded animals and also life-span extending
activity against warm-blooded animals having sufferred from tumors.
Consequently, the pharmaceutical preparations which contain the
compounds (I) or their salts can be used as a safe antitumor agent
intended for the treatment of tumors in warm-blooded animals,
particualrly mammals (e.g., mice, rats, cats, dogs, rabbits,
etc.).
In the case of being utilized as an antitumor agent, the compound
(I) or its salt can be administered orally or parenterally as such
or after being processed into various dosage forms, such as
powders, granules, tablets, capsules, suppositories and injections,
by means of the conventionally employed procedures with use of
pharmacologically allowable carriers, excipients, diluents, etc.
Although the dosage amounts vary depending upon the species of
animals to be treated, kind of diseases, symptoms, type of
compounds, route of administration and the like, the compound (I)
or its salt may be administered to the above-described warm-blooded
animals, for example, in the case of oral administration, at daily
doses in the range of about 2.0 to 200 mg/kg body weight,
preferably 5.0 to 100 mg/kg body weight, or, in the case of
parenteral administration, at daily doses in the range of about 1.0
to 100 mg/kg body weight, preferably 2.5 to 50 mg/kg body weight.
As the method of administration by injections, there may be
mentioned intramuscular injection, intraperitoneal injection,
subcutaneous injection, intravenous injection and the like.
The above-mentioned procedure of processing into dosage forms can
be carried out following the per se known methods. The above
preparations for oral administration, for example, tablets, can be
prepared by suitably incorporating binders (e.g., hydroxypropyl
cellulose, hydroxypropyl methycellulose, macrogoal, etc.),
disintegrating agents (e.g., starch, carboxymethyl cellulose
calcium, etc.), lubricating agents (e.g., magnesium stearate, talc,
etc.) and the like.
The preparations for parenteral administration, for example,
injectable solutions, can be produced by suitably incorporating
tonicity agents (e.g., glucose, D-sorbitol, D-mannitol, sodium
chloride, etc.), preservatives (e.g., benzyl alcohol,
chlorobutanol, methyl p-oxybenzoate, propyl p-oxybenzoate, etc.),
buffers (e.g., phosphate buffer, sodium acetate buffer, etc.) and
the like.
By way of specific example of preparing tablets, on the basis of
amounts per tablet, about 1.0 to 25 mg of the compound (I) of this
invention or its salt, 100 to 500 mg of lactose, about 50 to 100 mg
of corn starch and about 5 to 20 mg of hydroxypropyl cellulose are
mixed by means of the conventional procedure, and the mixture is
granulated, followed by mixing with corn starch and magnesium
stearate and compressing into a tablet weighing about 100 to 500 mg
and measuring about 3 to 10 mm in diameter. Such tablets produced
can be provided with coating by use of an acetone-ethanol mixed
solution having hydroxypropylmethyl methylcellulose (about 10 to 20
mg) and castor oil (about 0.5 to 2 mg) dissolved at a concentration
of about 5 to 10% (the amounts are on the basis of amounts per
tablet) to thereby produce enteric coated tablets.
By way of specific example of preparing injectable solutions, on
the basis of amounts used per ampoule, for example, a solution of
about 2.0 to 50 mg of sodium salt of the compound (I) of this
invention in about 2 ml of isotonic saline, is filled into an
ampoule, which is then fused and heat-sterilized at about
110.degree. C. for about 30 minutes, or about 2.0 to 50 mg of the
said sodium salt is dissolved in a solution of about 10 to 40 mg of
mannitol or sorbitol in about 2 ml of sterilized distilled water,
and the resulting solution is filled into an ampoule, followed by
lyophilizing and fusing to produce the injections. On the occasion
of use, the seal of the lyophilized preparation is opened, and the
active compound is dissolved, for example, with physiological
saline so as to make a solution having the compound in a
concentration of about 1.0 to 25 mg/ml, thereby an injectable
solution intended for subcutaneous, intravenous or intramuscular
administration is provided.
As is described above, the production process of this invention
starts with cheap and industrially available raw materials and can
provide antitumor agents being highly useful as a drug in shortened
steps and in increased yields. In addition, the process is
practically simplified and facilitated in terms of reaction
processability and workability, and is more favored from the
standpoint of the production facilities, thus providing an
industrially advantageous process for producing 5-substituted
pyrrolo[2,3-d]pyrimidine derivatives.
Described below are the reference examples and examples to
illustrate this invention specifically.
REFERENCE EXAMPLE 1
Production of tert-butyl 4-(4-methoxy-3-butenyl)benzoate:
A 1.0 mole tetrahydrofuran solution (11.0 ml) of potassium
tert-butoxide was added to a toluene solution (12 ml) of
(methoxymethyl)triphenylphosphonium chloride (3.77 g) at 0.degree.
C., and after stirring for 10 minutes, a toluene solution (10 ml)
of tert-butyl 4-(3-oxopropyl)benzoate (2.34 g) was added dropwise
to the mixture at the same temperature, followed by stirring at
0.degree. C. for 20 minutes. The reaction solution was admixed with
ether (40 ml), and the organic layer was separated, then washed
successively with water and saturated aqueous solution of sodium
chloride, and dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure, and the thus obtained residue
was treated with hexane, followed by filtering out the resultant
triphenylphosphine oxide. The filtrate was concentrated under
reduced pressure, and the residue was purified by column
chromatography (80 g of silica gel; ether-hexane=20:1) to give the
subject compound (1.92 g).
IR (neat): 2980, 2945, 1715, 1655, 1610, 850 cm.sup.-1. .sup.1
H-NMR (CDCl.sub.3): 1.59(9H,s), 2.24(1.2H,td,J=8 Hz,7 Hz),
2.39(0.8H,td,J=8Hz,7 Hz), 3.48(1.8H,s), 3.56(1.2H,s),
4.33(0.4H,td,J=7 Hz,6 Hz), 4.71(0.6H,dt,J=13 Hz,7 Hz),
5.88(0.4H,d,J=6 Hz), 6.28(0.6H,d,J=13 Hz), 7.21(2H,d,J=8 Hz),
7.91(2H,d,J=8 Hz).
REFERENCE EXAMPLE 2
Production of tert-butyl
4-[4,4-dicyano-3-(dimethoxymethyl)butyl]benzoate:
Under argon atmosphere, bromomalononitrile (1.27 and the compound
(1.91 g) as obtained in Reference Example 1 were dissolved in
dichloromethane (66 ml), and after addition of molecular sieve (3A,
1.0 g), the reaction mixture was irradiated with ultraviolet rays
for 2 hours by use of an ultraviolet lamp for analytical use having
the cover removed. Methanol (4 ml) was added to the reaction
mixture, which was stirred for 10 minutes and poured into ice water
containing 2N aqueous potassium carbonate solution (5 ml), followed
by extraction with dichloromethane. The organic layer was washed
with water and dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by column chromatography (75 g of silica gel; ethyl
acetate-hexane =1:10) to give the subject compound (2.08 g) in the
form of a colorless oily substance.
IR (Neat): 2980, 294 5, 2840, 2250, 1710, 1606, 845 cm.sup.-1.
.sup.1 H-NMR (CDCl.sub.3): 1.60(9H,s), 1.90-2.20(2H,m),
2.20-2.32(1H,m), 2.89(2H,t,J=8 Hz), 3.39(3H,s), 3.46(3H,s),
4.13(1H,d,J=4 Hz), 4.36(1H,d,J=5 Hz), 7.28(2H,d,J=8 Hz),
7.95(2H,d,J=8 Hz).
REFERENCE EXAMPLE 3
Production of tert-butyl 4-(5-methoxy-4-pentenyl)benzoate:
By following the same procedure as described in Reference Example
1, tert-butyl 4-(4-oxobutyl)benzoate (993 mg) was treated with
(methoxymethyl)triphenylphosphonium chloride to give the subject
compound (918 mg) in the form of a colorless oily substance.
IR (Neat): 2980, 2940, 2860, 1710, 1660, 1603, 860, 845 cm.sup.-1.
.sup.1 H-NMR (CDCl.sub.3): 1.55-1.76(2H,m), 1.59(9H,s),
1.96(0.6H,dt,J=7 Hz,7 Hz), 2.10(0.4H,tdd,J=7Hz,7 Hz,7 Hz),
2.66(2H,t,J=8 Hz), 3.51(1.8H,s), 3.59(1.2H,s),4.35(0.4H,td, J=7
Hz,6 Hz), 4.73(0.6H,dt,J=13 Hz,7 Hz), 5.91(0.4H,dt,J=6 Hz, 1 Hz),
6.29(0.6H,d,J=13 Hz), 7.21(2H,d,J=8 Hz), 7.89(0.SH,d, J=8 Hz),
7.90(1.2H,d,J=8 Hz).
REFERENCE EXAMPLE 4
Production of tert-butyl
4-[5,5-dicyano-4-(dimethoxymethyl)pentyl]benzoate:
By following the same procedure as described in Reference Example
2, the compound (276 mg) as obtained in Reference Example 3 was
reacted with bromomalononitrile to give the subject compound (202
mg) in the form of a colorless oily substance.
IR (Neat): 2975, 2930, 2245, 1710, 1605, 860, 845 Cm.sup.-1. .sup.1
H-NMR (CDCl.sub.3): 1.59(9H,S), 1.60-1.92(4H,m), 2.20-2.30(1H,m),
2.73(2H,t,J=7 Hz), 3.40(3H,s), 3.45(3H,s), 4.11(1H,d,J=4Hz),
4.31(1H,d,J=5 Hz), 7.24(2H,d,J=8 Hz), 7.93(2H,d,J=8 Hz).
REFERENCE EXAMPLE 5
Production of tert-butyl 4-(6-methoxy-5-hexenyl)benzoate:
By following the same procedure as described in Reference Example
1, tert-butyl 4-(5-oxobutyl)benzoate (476 mg) was treated with
(methoxymethyl)triphenylphosphonium chloride to give the subject
compound (430 mg) in the form of a colorless oily substance.
IR (neat): 2940, 1715, 1650, 1605, 1455, 850 cm.sup.-1. .sup.1
H-NMR (CDCl.sub.3): 1.32-1.44(2H,m), 1.59(9H,s), 1.52-1.70(2H,m),
1.94(1.2H,td,J=8 Hz,7 Hz), 2.09(0.8H,td,J=8 Hz,7 Hz), 2.65(2H,t,J=8
Hz), 3.49(1.8H,s), 3.58(1.2H,s), 4.31(0.4H,td, J=7 Hz,6 Hz),
4.70(0.6H,dt,J=13 Hz,7 Hz), 5.88(0.4H,d,J=6 Hz), 6.28(0.6H,d,J=13
Hz), 7.21(2H,d,J=8 Hz), 7.90(2H,d,J=8 Hz).
REFERENCE EXAMPLE 6
Production of tert-butyl
4-[6,6-dicyano-5-(dimethoxymethyl)hexyl]benzoate:
By following the same procedure as described in Reference Example
2, the compound (420 mg) as obtained in Reference Example 5 was
reacted with bromomalononitrile to give the subject compound (432
mg) in the form of a colorless oily substance.
IR (Neat): 2940, 2250, 1715, 1610, 1455, 845 cm.sup.-1. .sup.1
H-NMR (CDCl.sub.3): 1.48-1.81(6H,m), 1.59(9H,s), 2.18-2.28(1H,m),
2.71(2H,t,J=7 Hz), 3.40(3H,s), 3.46(3H,s), 4.10(1H,d,J=4 Hz),
4.31(1H,d,J=5 Hz), 7.23(2H,d,J=8 Hz), 7.92(2H,d,J=8 Hz).
EXAMPLE 1
Production of tert-butyl
4-[3-(2,4,6-triamino-pyrimidin-5-yl)-4,4-dimethoxybutyl]benzoate:
Under argon atmosphere, a tert-butyl alcohol suspension (30 ml) of
guanidine hydrochloride (640 mg) was admixed with a tetrahydrofuran
solution (6.70 ml) of 1.0 mole of potassium tert-butoxide, followed
by stirring for 10 minutes, and a tert-butyl alcohol solution (10
ml) of the compound (2.00 g) of Reference Example 2 was added to
the mixture, followed by heating under reflux for 2 hours. The
reaction solution was poured into water (200 ml) containing 1.0N
aqueous potassium hydrogensulfate solution (1 ml), followed by
extraction with dichloromethane. The organic layer was dried over
anhydrous sodium sulfate, and the solvent was distilled off under
reduced pressure. The resulting residue was purified by column
chromatography (50 g of silica gel;
dichloromethane-methanol=30:1.fwdarw.15:1) to give the subject
compound (2.17 g) in the form of a colorless amorphous
substance.
IR (KBr): 3475, 3360, 3200, 2975, 2930, 1710, 1607, 1563, 1430,
843, 800 cm.sup.-1. .sup.1 H-NMR (CDCl.sub.3): 1.58(9H,s),
1.86-2.05(1H,m), 2.25-2.53(2H,m), 2.57-2.80(2H,m), 3.45(3H,s),
3.48(3H,s), 4.35(1H,d,J=3 Hz), 4.36(2H,brs), 4.48(2H,brs),
5.21(2H,brs), 7.18(2H,d,J=8Hz), 7.88(2H,d,J=8 Hz).
EXAMPLE 2
Production of diethyl
N-[4-[2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glut
amate:
The compound (200 mg) as obtained in Example 1 was dissolved in
trifluoroacetic acid (1 ml) and water (20 mg), followed by stirring
at room temperature for 2 hours. The trifluoroacetic acid was
distilled off under reduced pressure, followed by drying under
vacuum at 70.degree. C., and the resulting residue and
diethyl-glutamate hydrochloride (172 mg) were suspended in
dimethylformamide (2 ml). A dimethylformamide solution (2 ml) of
diethyl phosphorocyanidate (82 mg) was added to the suspension at
0.degree. C., followed by stirring for 15 minutes, and a
dimethylformamide solution (2 ml) of triethylamine (218 mg) was
added dropwise to the mixture at the same temperature, followed by
stirring at 0.degree. C. for 30 minutes and then at room
temperature for 2 hours. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by column
chromatography (15 g of silica gel; dichloromethane separated from
conc. ammonia.fwdarw.dichloromethane--10% ammoniacal ethanol
40:1.fwdarw.30:1) to give the subject compound (195 mg) in the form
of a colorless amorphous substance.
IR (KBr): 3375, 3200, 2980, 2930, 1735, 1640, 1605, 1572 cm.sup.-1.
.sup.1 H-NMR (CDCl.sub.3): 1.23(3H,t,J=7 Hz), 1.31(3H,t,J=7 Hz),
2.10-2.40(2H,m), 2.48(2H,dd,J=6 Hz,6 Hz), 3.00(4H,brs),
4.12(2H,q,J=7 Hz), 4.25(2H,q,J=7 Hz), 4.61(2H,brs), 4.75-4.86
(1H,m), 4.95(2H,brs), 6.40(1H,s), 7.13(1H,d,J=7 Hz), 7.22 (2H,d,J=8
Hz), 7.74(2H,d,J=8 Hz), 8.55(1H,brs).
EXAMPLE 3
Production of
N-[4-[2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glut
amic acid:
To a tetrahydrofuran-water mixed solution (2:1, 3 ml) of the
compound (80 mg) as obtained in Example 2 was added 1.0N aqueous
sodium hydroxide solution (0.497 ml), followed by stirring at room
temperature for 1 hour. The reaction solution was concentrated to a
total volume of 1.0 ml under reduced pressure, and after the
resulting insoluble matter was filtered through Millipore filter,
the filtrate was cooled at 0.degree. C. and admixed with acetic
acid (0.1 ml). The resulting crystals were recovered by filtration,
washed thoroughly with ice water and dried at 70.degree. C. under
reduced pressure to give the subject compound (61 mg) in the form
of white crystals.
IR (KBr): 3320, 1660, 1637, 1540 cm.sup.- 1. .sup.1 -NMR
(Me2SO-d6): 1.85-2.20(2H,m), 2.46(2H,t,J=8 Hz), 2.96(4H,brs),
4.30-4.45(1H,m), 5.49(2H,brs), 6.13(2H,s), 6.37(1H,s),
7.33(2H,d,J=8 Hz), 7.80(2H,d,J=8 Hz), 8.46(1H,d, J=7hz),
10.34(1H,brs).
EXAMPLE 4
Production of tert-butyl
[4-[4-(2,4,6-triaminopyrimidin-5-yl)5,5-dimethoxypentyl]benzoate
By following the same procedure as described in Example 1, the
compound (190 mg) as obtained in Reference Example 4 was reacted
with guanidine hydrochloride to give the subject compound (214 mg)
in the form of white powder. IR (KBr): 3480, 33 80, 3200, 2980,
2940, 1715, 1610, 1570, 1440, 850, 805 cm.sup.-1. .sup.1 H-NMR
(CDCl.sub.3): 1.40-1.65(3H,m), 1.59(9H,s), 1.75-2.05(1H,m),
2.62(2H,t,J=7 Hz), 2.81(1H,ddd,J=11 Hz,3 Hz,1 Hz), 3.46(3H,s),
3.50(3H,s), 4.36(1H,d,J=3 Hz), 4.49(4H,brs), 5.16(2H,brs),
7.18(2H,d,J=8Hz), 7.88(2H,d,J=8 Hz).
EXAMPLE 5
Production of tert-butyl
4-[3-(2,4-diamino-7-Hpyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoate
The compound (206 mg) as obtained in Example 4 was dissolved in
tetrahydrofuran-water mixed solution (3:1, 8 ml), and 1N
hydrochloric acid (4.8 ml) was added to the solution, followed by
stirring at room temperature for 18 hours. The reaction solution
was admixed with 1N sodium hydroxide solution (4.8 ml) for
neutralization, followed by extraction with dichloromethane, and
the extract layer was dried over anhydrous sodium sulfate and freed
of solvent under reduced pressure. The resulting residue was
purified by column chromatography (10 g of silica gel;
dichloromethane-methanol=15:1) to give the subject compound (126
mg) in the form of white crystals.
m.p. 172.degree.-173.degree. C. IR (KBr): 3335 , 3180 , 2975 , 2935
, 1710, 1607, 1287, 1163, 1110 cm.sup.-1. .sup.1 H-NMR
(Me2SO-d.sub.6): 1.54 (9H,s) , 1.77-1.90(2H,m) , 2.68(2H,t,J=8 Hz),
2.72(2H,t,J=8 Hz), 5.54(2H,brs), 6.11 (2H, brs), 6.45(1H,s),
7.33(2H,d,J=8 Hz), 7.82(2H,d,J=8 Hz), 10.51 (1H,s) .
EXAMPLE 6
Production of diethyl N-[4- [3- (2,4-diamino-7H-pyrrolo
2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamate:
(A) The compound (381 mg) as obtained in Example 5 was dissolved in
trifluoroacetic acid (3 ml), and the solution was stirred at room
temperature for 3 hours. The trifluoroacetic acid was distilled off
under reduced pressure, followed by drying at 70.degree. C. under
reduced pressure, and the resulting residue, together with diethyl
L glutamate hydrochloride (748 mg) was suspended in
dimethylformamide (4 ml). A dimethylformamide solution (4 ml) of
diphenylphosphoryl azide (858 mg) was added to the suspension at
0.degree. C., followed by stirring, and a dimethylformamide
solution (4 ml) of triethylamine (631 mg) was added dropwise to the
solution mixture at the same temperature, followed by stirring at
0.degree. C. for 30 minutes and then at room temperature for 63
hours. The solvent was distilled off under reduced pressure, and
the resulting residue was purified by column chromatography (15 g
of silica gel; dichloromethane separated from conc.
ammonia.fwdarw.dichloromethane separated from conc.
ammonia-ethanol=40:1.fwdarw.30:1) to give the subject compound (374
mg) in the form of colorless crystals.
(B) By following the same procedure as described in Example 2, the
subject compound can be produced from the compound as obtained in
Example 4.
IR (KBr): 3330, 3160, 1735, 1632, 1575, 1540, 1500, 1200 cm.sup.-1.
.sup.1 H-NMR (Me.sub.2 SO-d.sub.6): 1.17(3H,t,J=7 Hz), 1.20(3H,t,
J=7 Hz), 1.80-2.20(4H,m), 2.44(2H,t,J=7 Hz), 2.68(2H,t,J=7 Hz),
2.72(2H,t,J=7 Hz), 4.05(2H,q,J=7 Hz), 4.11(2H,q,J=7 Hz),
4.35-4.50(1H,m), 5.34(2H,s), 5.91(2H,s), 6.42(1H,s), 7.31(2H,d, J=8
Hz), 7.80(2H,d,J=8 Hz), 8.66(1H,d,J=8 Hz), 10.51(1H,s).
EXAMPLE 7
Production of
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glu
tamic acid:
By following the same procedure as described in Example 3, the
compound as obtained in Example 6 was subjected to a hydrolysis
reaction to give the subject compound (201 mg) in the form of white
crystals.
m.p. 220.degree.-221.degree. C. IR (KBr): 3340, 3200, 2940,
1660-1630, 1540, 1500, 1397 cm.sup.1. .sup.1 H-NMR (Me.sub.2
SO-d.sub.6): 1.75-2.20(4H,m), 2.35(2H,t,J=7 Hz), 2.68(2H,t,J=7Hz) ,
2.71 (2H,t,J=7 Hz) , 4.30-4.47(1H,m) , 5.53(2H,brs), 6.15(2H,s),
6.46(1H,s), 7.31(2H,d,J=8 Hz), 7.81(2H,d,J=8 Hz), 8.48(1H,d,J=8
Hz), 10.51(1H,s).
EXAMPLE 8
Production of tert-butyl
4-[5-(2,4,6-triaminopyrimidin-5-yl)-6,6-dimethoxyhexyl]benzoate:
By following the same procedure as described in Example 1, the
compound (378 mg) as obtained in Reference Example 6 was reacted
with guanidine hydrochloride to give the subject compound (433 mg)
in the form of white crystals.
IR (KBr): 3475, 3360, 3220, 2975, 2930, 1715, 1640, 1607, 1563,
1435, 843, 800 cm.sup.1. .sup.1 H-NMR (CDCl.sub.3):
1.14-1.32(2H,m), 1.45-1.72(3H,m), 1.58(9H,s), 1.86-2.04(1H,m),
2.56-2.68(2H,m), 2.72-2.83 (1H,m), 3.47(3H,s), 3.52(3H,s),
4.39(1H,d,J=3 Hz), 4-36(2H, brs), 4.48(2H,brs), 5.21(2H,brs),
7.18(2H,d,J=8 Hz), 7.88(2H, d,J=8 Hz) .
EXAMPLE 9
Production of diethyl
N-[4-[4-(2,4-diamino-7H-pyrrolo-[2,3-d]pyrimidin-5-yl)
butyl]benzoyl ]-L-glutamate:
By following the same procedure as described in Example 2, the
compound (230 mg) as obtained in Example 8 yielded the subject
compound (228 mg) in the form of white powder.
IR (KBr): 3380, 3200, 2980, 2930, 1735, 1640, 1605, 1572 cm.sup.31
1. .sup.1 H-NMR (CDCl.sub.3 /CD.sub.3 OD): 1.22(3H,t,J=7 Hz) , 1.31
(3H,t, J=7 Hz), 1.60-1.83(4H,m), 2.43-2.51(2H,m), 2.63-2.76(4H,m),
4.11(2H,q,J=7 Hz), 4.24(2H,q,J=7 Hz), 4.74-4.86(1H,m), 6.45(1H,s),
7.24(2H,d,J=8 Hz), 7.74(2H,d,j=8 Hz) .
EXAMPLE 10
Production of N-[4-[4-(2,4-diamino-7H-pyrrolo[2,3-d]
pyrimidin-5-yl)butyl]benzoyl]-L-glutamic acid:
By following the same procedure as described in Example 3, the
compound (103 mg) as obtained in Example 9 was subjected to a
hydrolysis reaction to give the subject compound (72 mg) in the
form of white crystals.
IR (KBr): 3340, 3200, 2930, 1650, 1635, 1540 cm.sup.-1.
.sup.1 -NMR (Me.sub.2 SO-d.sub.6): 1.45-1.7 6(4H,m),
1.88-2.19(2H,m), 2.29-2.43(2H,m) , 2.58-2 .76(4H,m), 4
.32-4.46(1H,m), 5.54(2H, brs) , 6.16 (2H, brs) , 6 . 4 2(1H,s), 7.2
9(2H,d,J=8 Hz), 7.79(2H,d, J=8 Hz) , 8.52(1H,d,J=7 Hz), 10.48(1H,
brs).
EXAMPLE 11
Production of diethyl N-[4-[3-(2,4-diamino-5,6-6,7-dihydro 5H
pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamate:
The compound (20 mg) as obtained Example 9 was dissolved in 2%
hydrochloric-acid ethanol solution (20 ml), and after addition of
platinum oxide (3 mg), catalytic reduction was carried out under
hydrogen atmosphere for 12 hours. The catalyst was removed by
filtration, and the filtrate was concentrated to dryness. The
resulting residue was purified by column chromatography (2.0 g of
silica gel; dichloromethane separated from conc. ammonia
dichloromethane separated from conc.
ammonia-ethanol=40:1.fwdarw.30:1) to give the subject compound (4.8
mg).
IR (KBr): 3350, 2990, 2945, 1740, 1610, 1540, 1508, 1438 cm.sup.-1.
.sup.1 H-NMR (CDCl.sub.3): 1.23(6H,tx2,J=7 Hz), 1.43-1.80(3H,m),
1.85-2.77(7H,m), 2.95-3.30(2H,m), 3.58(1H,t,J=11 Hz), 4.07
(2H,q,J=7 Hz), 4.20(2H,q,J=7 Hz), 4.25(1H,brs), 4.63-4.83 (1H,m),
4.68(1H,brs), 7.00-7.23(1H,m), 7.13(2H,d,J=8 Hz), 7.67(2H,d,J=8
Hz).
EXAMPLE 12
Production of N-[4-[3-(2,4-diamino-6,7-dihydro-5H
[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid:
By following the same procedure as described in Example 3, the
compound (4.4 mg) as obtained in Example 11 was subjected to a
hydrolysis reaction to give the subject compound (3.2 mg).
IR (KBr): 3700-2350, 3215, 1690-1620, 1540 cm.sup.-1. .sup.1 H-NMR
(Me.sub.2 SO-d.sub.6): 1.02-1.85(4H,m), 1.85-2.83(6H,m),
2.90-3.30(2H,m), 3.55(1H,t,J=11 Hz), 4.15-4.45(1H,m), 6.38
(2H,brs), 6.77(2H,brs), 6.90(1H,brs), 7.22(2H,d,J=8 Hz),
7.74(2H,d,J=8 Hz), 8.22(1H,d,J=7 Hz).
EXAMPLE 13
Production of ethyl
4-[4-(2,4,6-triaminopyrimidin-5-yl)-5,5-dimethoxypentyl]benzoate:
Under argon atmosphere, a solution (0,612 ml) of 1.0 mole of sodium
ethoxide in ethyl alcohol was added to a suspension (1.0 ml) of
guanidine hydrochloride (58.5 mg) in ethyl alcohol. To this
solution, a solution (3.0 ml) of ethyl
4-[5,5-dicyano-4-(dimethoxymethyl)pentyl]benzoate* (190 mg) in
ethyl alcohol was added and the mixture was refluxed under heating
for 2 hours.
The reaction mixture was poured into water (10 ml), extracted with
dichloromethane, and the organic layer was dried with anhydrous
sodium sulfate. Solvent was removed from the extract by
distillations under reduced pressure and the residue was purified
by flash column chromatography (15 g of silica gel;
dichloromethane-methanol =30:1.fwdarw.15:1) to give the subject
compound (214 mg) .
IR(KBr): 3460, 3340, 3180, 2940, 1710, 1610, 1565, 1435, 1275,
1110, 1060, 805 cm.sup.-1. .sup.1 H-NMR(CDCl.sub.3):
1.38(3H,t,J=7.2 Hz), 1.43-1.70(3H, m), 1.83-2.05(1H,m),
2.63(2H,t,J=7 Hz), 2.77-2.87(1H,m), 3.46(3H,s), 3.50(3H,s),
4.36(2H,q,J=7.2 Hz), 4.37(1H,d,J=3.6 Hz), 4.45(4H,brs),
5.10(2H,brs), 7.20(2H,d,J=8 Hz), 7.94(2H,d,J=8 Hz)
EXAMPLE 14
Production of ethyl 4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]
pyrimidin-5-yl)propyl]benzoate:
To the suspension (2.0 ml) of the product in Example 13 (404 mg) in
ethyl alcohol, ethyl alcohol containing 20% (w/w) of hydrogen
chloride (2.0 ml) and water (0.02 ml) were added, and the mixture
was stirred at room temperature for 2 hours. The reaction mixture
was diluted with water (10 ml) and made alkaline by adding aqueous
ammonia thereto, followed by removing most part of ethyl alcohol
therefrom by distillation under reduced pressure. Resulting
precipitates were collected by filtration, washed with water,
alcohol and ether, successively, and dried to give the subject
compound (300 mg) .
IR(KBr): 3330, 3225, 2930, 1705, 1610, 1575, 1490, 1450, 1410,
1280, 1180, 1105, 1020, 830 cm.sup.-1. .sup.1 H-NMR(CDCl.sub.3
/CD.sub.3 OD): 1.39(3H,t,J=7.2 Hz), 2.05(2H,m), 2.67(2H,t,J=7.2
Hz), 2.78(2H,t,J=7.2 Hz), 4.37(2H, q,J=7.2 Hz), 6.50(1H,s),
7.27(2H,d,J=8 Hz), 7.98(2H,d,J=8 Hz)
EXAMPLE 15
Production of
4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoic
acid:
The product of Example 14 (340 mg) was suspended in a mixed
solution of tetrahydrofuran-water (5:1, 6.0 ml), 1 N aqueous
solution of sodium hydroxide (4.0 ml) was added thereto, and the
mixture was stirred at 50.degree. C. for 18 hours. Most part of
tetrahydrofuran was removed from the mixture by distillation under
reduced pressure and the residue was neutralized by adding 1 N
hydrochloric acid thereto. Resulting precipitates were collected by
filtration, washed with water, methanol and ether, successively,
and dried under reduced pressure to give the subject compound (305
mg) .
IR(KBr): 3480, 3390, 3130, 2940, 1650, 1605, 1550, 1460, 1390,
1255, 1180, 1095, 980, 780 cm.sup.-1. .sup.1 H-NMR(Me.sub.2
SO-d.sub.6): 1.73-1.95(2H,m), 2.67(2H,t,J=7 Hz), 2.71 (2H,t,J=7 Hz)
, 5.37(2H,s), 5.95(2H,s), 6.43(1H,s), 7.33(2H,d,J=8Hz),
7.86(2H,d,J=8 Hz), 10.40(1H,s)
EXAMPLE 16
Production of diethyl
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl]propyl]benzoyl]-L-glu
tamate:
The product of Example 15 (339 mg) and diethyl glutamate
hydrochloride (748 mg) were suspended in dimethylformamide (4.0
ml), a solution (4.0 ml) of diphenylphosphoryl azide (858 mg) in
dimethylformamide was added thereto at 0.sup..degree. C and
stirred. Subsequently, a solution (4.0 ml) of triethylamine (631
mg) in dimethylformamide was added dropwise thereto at the same
temperature, and the mixture was stirred at 0.degree. C. for 30
minutes and then at room temperature for 63 hours, followed by
removing solvent by distillation under reduced pressure. Resulting
residue was purified by column chromatography (15 g of silica gel;
dichloromethane separated from conc. ammonia dichloromethane
separated from conc. ammonia-ethanol=40:1 30:1) to give the subject
compound (386 mg) as colorless crystals.
IR(KBr) and .sup.1 H-NMR(Me.sub.2 SO-d.sub.6) of the compound were
completely identical with those of the product in Example 6.
EXAMPLE 17
Production of diethyl
N-[4-[4-(2,4,6-triaminopyrimidin-5-yl)-5,5-dimethoxypentyl]benzoyl]-L-glut
amate:
The product of Example 13 (403 mg) was suspended in a mixed
solution of tetrahydrofuran-water (5:1, 8.0 ml), I N aqueous
solution of sodium hydroxide (2.0 ml) was added thereto and the
mixture was stirred at 40.degree. C. overnight. After neutralizing
the mixture by adding 1N hydrochloric acid (2.0 ml), solvent was
removed by distillation under reduced pressure and the residue was
dried to give crude
4-[4-(2,4,6-triaminopyrimidin-5-yl)-5,5-dimethoxypentyl]benzoic
acid. The total amount of the crude product and diethyl L-glutamate
hydrochloride (360 mg) were suspended in dimethylformamide (4.0
ml), a solution (4.0 ml) of diethyl phosphorocyanidate (171 mg) in
dimethylformamide was added thereto at 0.degree. C. and the mixture
was stirred. Subsequently, a solution (4.0 ml) of triethylamine
(303 mg) in dimethylformamide was added dropwise thereto at the
same temperature and the mixture was stirred at 0.degree. C. for 30
minutes and then at room temperature for 3 hours, followed by
removing solvent by distillation under reduced pressure. The
resulting residue was purified by flash column chromatography (15 g
of silica gel; dichloromethane-methano 30:1.fwdarw.5:1) to give the
subject compound (417 mg).
.sup.1 -HNMR(CDCl.sub.3 /CD.sub.3 OD): 1.22(3H,t,J=7 Hz),
1.32(3H,t,J=7 Hz) , 1.52-1.74(2H,m), 1.93-2.38(4H,m),
2.45-2.56(2H,m), 2.63(2H,t,J=7.4 Hz), 2.77-2.87(1H,m), 3.48(3H,s),
3.51(3H,s), 4.12(2H,q,J=7 Hz), 4.25(2H,q,J=7 Hz), 4.35(1H,d,J=3.2
Hz), 4.77-4.85(1H,m), 7.21(1H,d,J=8.4 Hz), 7.94(2H,d,J=8.4 Hz)
EXAMPLE 18
Production of diethyl
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glu
tamate:
To a suspension of the product of Example 17 (100 mg) in ethyl
alcohol (2.0 ml), ethyl alcohol containing 20% (w/w) of hydrogen
chloride (2.0 ml) and water (0.02 ml) were added and the mixture
was heated at room temperature for 2 hours. The reaction mixture
was diluted with water (10 ml), and neutralized by adding aqueous
ammonia thereto, followed by removing solvent therefrom by
distillation under reduced pressure. The resulting residue was
purified by column chromatography (15 g of silica gel;
dichloromethane separated from conc. ammonia.fwdarw.dichloromethane
separated from conc. ammonia-ethanol=40:1.fwdarw.30:1) to give the
subject compound (68 mg).
IR(KBr) and .sup.1 H-NMR(Me.sub.2 SO-d.sub.6) of the compound were
identical with those of the product in Example 6.
EXAMPLE 19
Production of
4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoic
acid:
Methyl
4-[4-(2,4,6-triaminopyrimidin-5-yl)-5,5-dimethoxypentyl]benzoate
(2.15 g), obtained from methyl 4-4-(4-oxobutyl)benzoate employing
procedures of Reference Example 3, Reference Example 2 and Example
13 in this order, was dissolved in a mixed solution of
tetrahydrofuran (15.5 ml) and 1N hydrochloric acid (7.1 ml), and
the mixture was stirred at 68.sup..degree. C for 1 hour. Methyl
4-[3-(2,4-diamino-7H-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]benzoate
produced in the reaction mixture was not isolated in this stage. To
the reaction mixture, methanol (5.7 ml) and a aqueous solution
(2.85 ml) of sodium hydroxide (0.684 g) were directly added and
hydrolysis was carried out at 67.degree. C. for 1 hour. Organic
solvent in the reaction mixture was removed by distillation under
reduced pressure and there remain an aqueous solution which was
adjusted to pH 3 with 6N hydrochloric acid. Resulting precipitates
were collected by filtration, washed with a small amount of water
and dried under reduced pressure to give the subject compound (1.72
g). IR(KBr) and .sup.1 H-NMR(Me.sub.2 SO-d.sub.6) of the compound
were completely identical with the product of Example 15.
In the same manner as in Examples 1 to 19, the following compounds
can be synthesized.
(1) Dibenzyl
N-[4-[3-(2-amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]
-L-glutamate,
(2)
N-[4-[3-(2-amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]
-L -glutamic acid,
(3)
N-[4-[3-(2-amino-4-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]pro
pyl]benzoyl]-L-glutamic acid,
(4) Di(p-methoxybenzyl)
N-[4-[3-(2-amino-4-mercapto-7H-pyrrolo(2,3-d]pyrimidin-5-yl)propyl]benzoyl
]-L-glutamate,
(5)
N-[4-[3-(2-amino-4-mercapto-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl
]-L-glutamic acid,
(6)
N-[4-[3-(2-amino-4-mercapto-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)pr
opyl]benzoyl]-L-glutamic acid.
(7)
N-[4-[3-(2,4-diamino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzo
yl]-L-glutamic acid,
(8)
N-[4-[3-(2,4-diamino-6-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-6-yl)
propyl]benzoyl]-L-glutamic acid,
(9)
N-[4-[3-(2,4-diamino-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoy
l]-L-glutamic acid,
(10)
N-[4-[3-(2,4-diamino-6-ethyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)p
ropyl]benzoyl]-L-glutamic acid,
(11)
N-[4-[3-(2,4-diamino-6-vinyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoy
l]-L-glutamic acid,
(12)
N-[4-[3-(2,4-diamino-6-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benz
oyl]-L-glutamic acid,
(13)
N-[4-[3-2,4-diamino-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl
]benzoyl]-L-glutamic acid,
(14)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-methylpropyl]benzo
yl]-L-glutamic acid,
(15)
N-[4-[3-(2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-methyl
propyl]benzoyl]-L-glutamic acid,
(16)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5,yl)-1-hydroxymethylpropy
l]benzoyl]-L-glutamic acid,
(17)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(formylmethyl)prop
yl]benzoyl]-L-glutamic acid,
(18)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-chloromethylpropyl
]benzoyl]-L-glutamic acid,
(19)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-dichloromethylprop
yl]benzoyl]-L-glutamic acid,
(20)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-trifluoromethylpro
pyl]benzoyl]-L-glutamic acid,
(21)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-methoxymethylpropy
l]benzoyl]-L-glutamic acid,
(22)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-ethoxymethylpropyl
]benzoyl]-L-glutamic acid,
(23)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-cyanomethylpropyl]be
nzoyl]-L-glutamic acid,
(24) N-[4-[3-(2,4-diamino-7H-pyrrlo[2,3-d]pyrimidin-5-yl)-
1-(methylthiomethyl)propyl]benzoyl]-L-glutamic acid,
(25)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpropyl]benzo
yl]-L-glutamic acid,
(26)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylpropyl]benzo
yl]-L-glutamic acid,
(27)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1,1-dimethylpropyl]b
enzoyl]-L-glutamic acid,
(28)
N-[4-[3-(2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)-l,l-dime
thylpropyl]benzoyl]-L-glutamic acid,
(29)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,2-dimethylpropyl]b
enzoyl]-L-glutamic acid,
(30)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-ethylpropyl]benzoy
l]-L-glutamic acid,
(31)
N-[4-[3-(2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-ethylp
ropyl]benzoyl]-L-glutamic acid,
(32)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-hydroxyethylpropyl
]benzoyl]-L-glutamic acid,
(33)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(2-formylethyl)pro
pyl]benzoyl]-L-glutamic acid,
(34) N-[4-[3-(2,4-diamino-7H-pyrrolo[2
,3-d]pyrimidin-5-yl)-1-methoxyethylpropyl]benzoyl]-L-glutamic
acid,
(35)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-ethoxyethylpropyl]
benzoyl]-L-glutamic acid,
(36)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-ethylpropyl]benzoy
l]-L-glutamic acid,
(37)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-vinylpropyl]benzoy
l]-L-glutamic acid,
(38)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-vinylpropyl]benzoy
l]-L-glutamic acid,
(39)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-allylpropyl]benzoy
l]-L-glutamic acid,
(40)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-ethynylpropyl]benz
oyl]-L-glutamic acid,
(41)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(iso-propyl)propyl
]benzoyl]-L-glutamic acid,
(42)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(2-propen-1-yl)pro
pyl]benzoyl]-L-glutamic acid,
(43)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-propargylpropyl]be
nzoyl]-L-glutamic acid,
(44)
N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(2-propyn-1-yl)pro
pyl]benzoyl]-L-glutamic acid,
(45) Methyl
4-[4-(2,4,6-triaminopyrimidin-5-yl)-5,5-dimethoxypentyl]benzoate,
(46) Benzyl
4-[4-(2,4,6-triaminopyrimidin-5-yl)-5,5-dimethoxypentyl]benzoate,
(47) p-Methoxybenzyl
4-[4-(2,4,6-triaminopyrimidin-5-yl)-5,5-di(methylthio)pentyl]benzoate,
(48) Dibenzyl
N-[4-[4-(2,4,6-triaminopyrimidin-5-yl)-5,5-dimethoxypentyl]benzoyl]-L-glut
amate.
(49) Methyl
4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoate,
(50) Benzyl
4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoate.
* * * * *